Zolpidem (Ambien®) is a therapeutic agent thought to interact with the benzodiazepine receptor within the GABAA receptor complex. As such, zolpidem shares much of its pharmacology with the benzodiazepines. Zolpidem, however, is more selective, interacting primarily with the ω1 receptor, which explains the lesser degree of myorelaxant and anticonvulsant effects observed in animal studies, relative to the benzodiazepines. Eszopiclone (Lunesta®, Sepracor), indiplon (Pfizer), gaboxadol (Merck), and zaleplon (Sonata®, King) are also important members of this class of purported GABAA modulators.

Ambien® is converted in vivo by oxidative and conjugative degradation to multiple metabolites. The major metabolites include phase I metabolism leading to demethylation at the nitrogen center and benzylic and imidazopyridyl hydroxylation, as well as significant phase II metabolism including glucuronidation of the hydroxylated metabolites. Zolpidem is metabolized in part by polymorphically expressed isozymes of cytochrome P450, including CYP2C9. The activity of zolpidem is cut short primarily by oxidation of the benzylic methyl group. The oxidation of this group accounts for approximately 84% of the net intrinsic clearance. The imidazopyridyl methyl group oxidation accounts for approximately another 12% of net intrinsic clearance. As such, zolpidem does not provide adequate duration of action for many patients. Consequently, its application in polypharmacy is necessarily complex, has potential for adverse events, and increases inter-patient variability in response to polypharmacy.
There is therefore a need for hypnotic agents which can provide adequate duration of action to patients in need.